1.1 Field of the Invention
The present invention relates generally to the field of pharmacology. More particularly, it concerns novel anabaseine related compounds and methods of using these compounds for treating conditions associated with defects or malfunctioning of nicotinic subtype brain receptors.
1.2 Description of the Related Art
There are many nicotinic receptor subtypes found in brain. Nicotine is a drug that can apparently activate all of these receptor subtypes, as can the endogenous transmitter acetylcholine. Nicotine itself has both positive and negative attributes in humans, depending on the receptor subpopulation involved. The quantitatively two predominant receptor subtypes in brain are alpha7 and alpha4beta2.
A variety of molecular, biochemical and physiological studies demonstrate the presence of multiple nicotinic receptor subunits in brain and other tissues. One of the predominant nicotinic receptor subtypes in the brain contains the .alpha.7-subunit, especially in telencephalic regions such as hippocampus and neocortex. These receptors function as homo-oligomers when expressed in oocytes, where they demonstrate characteristic high affinity binding to .alpha.-bungarotoxin, high calcium-permeability, and rapid desensitization. Recent studies with selective .alpha.7 agonists suggest that these receptors are involved in memory related behaviors as well as in the maintenance of intracellular calcium-homeostasis.
The best studied selective .alpha.7 agonist is GTS-21, (E-3-[2,4-dimethoxy-benzylidene] anabaseine, also referred to as DMXB). GTS-21 enhances performance in several spatial and non-spatial memory-related paradigms in rats and rabbits. It also exerts neuroprotective activity against trophic factor deprivation in PC12 cells (Martin, et al., 1994), NMDA-receptor activation in primary neuronal cultures (Shimohama, et al., in press), and fimbrial transections in vivo (Meyer, et al. in press). Despite these behavioral and neuroprotective actions of GTS-21, however, it is only a modestly efficacious partial agonist at .alpha.7 receptors, with about 20% of the activity of ACh itself.
A fully efficacious and potent .alpha.7 agonist has been described, the 3-cinnamylidene substituted anabaseine, DMAC or E,E-3-(4-dimethylaminocinnamylidene) anabaseine.
This compound also has memory-enhancing activity in rodents, but no neuroprotective activity has not been documented. DMAC also possesses the unusual property of inducing a long term inhibition of .alpha.7 receptors following activation. While the biological significance of this inhibitory activity is not presently known, it might be expected to interfere with long term actions of the compound dependent on receptor activation such as neuroprotection.
With respect to structure activity differences between GTS-21 and DMAC, it is not known to what extent either the full agonist efficacy or the pronounced antagonist activity of the latter compound derives from its cinnamylidene-anabaseine structure or from other substituent differences.
1.2.1 Nicotine and Smoking
Nicotine is both the reinforcing and addictive agent present in tobacco smoke. In smoking addiction, all N-acetylcholine receptor subtypes are potentially activated by nicotine, including those not directly involved in producing reinforcement. Currently available replacement therapies such as nicotine-containing gums and patches, also activate all receptor subtypes. While nicotine gum and patches block some withdrawal symptoms, they also produce reinforcement. While difficult to quantify, the level of reinforcement produced by nicotine gum and patches does not appear as great as that produced by smoking, thought to be because gum and patches are not as effective as cigarettes at delivering nicotine to produce reinforcement. (de Fiebre, et al.; Collins, et al.) Hence, abuse of gum or patches does not appear to be a major problem when these products are used in smoking cessation programs. However, the rate of recidivism following the use of gum or patches remains almost as high as when no replacement therapy is provided. Although gum and patches attenuate withdrawal symptoms, their suboptimal reinforcing properties may prolong craving in recovering smokers and contributes to the high rate of smoking recidivism following their use.
Substances which inhibit the activation of nicotine receptors mediating the psychological reward/addiction properties of tobacco, administered by smoking or orally as a powder (called "snuff"), provide the ultimate therapy for acquiring a state of tobacco abstinence. This has not previously been achieved because known nicotine receptor antagonists (examples: mecamylamine, tubocurarine) are not selective for these particular nicotine receptors. Such antagonists act upon the autonomic nervous system, and at the neuromuscular synapse, causing a variety of toxic side effects, including autonomic block (causing a variety of changes including hypotension) and neuromuscular block (causing respiratory depression).
1.2.2 Ethanol and nicotine
It is well documented that smoking and drinking are positively correlated to the extent that those who smoke usually also drink and vice versa. It has been shown that ethanol can increase smoking behavior (Burton and Tiffany, 1997). Studies in rats have shown that nicotine administration can increase ethanol consumption (Blomquist, et al., 1996). Other studies have shown that cross-tolerance develops between ethanol and nicotine (Collins, et al., 1996) and that sensitivity to ethanol and nicotine are genetically correlated (de Fiebre, et al., 1992). This has suggested that ethanol and nicotine may share a common site(s) of action at one or more nicotinic receptor subtypes. Recent studies have determined that apparently the alpha7 nicotinic receptor subtype is affected by ethanol (Yu, et al., 1996).
It has been speculated that activation of brain alpha7 receptors may be implicated in the propagation of certain types of seizures (e.g., nicotine-induced seizures, (Marks et al., 1989; Miner and Collins, 1989).
1.2.3 Ischemia
Ischemia and resulting glutamate-release are a principle cause of neuronal loss in strokes, drowings and other insults to the brain. Glutamate is recognized as the principle excitotoxin responsible for much of the cell death following ischemic attack.
Nicotinic receptors have been well characterized at the neuromuscular junction as well as in electric organs of species such as Torpedo californica, where they form pentemetic transmembrane rings of four subunits termed .alpha., .beta., .delta. and .gamma. (Deneris, et al., 1991). Less is known about brain nicotinic receptors, however, with ligand-binding, electrophysiological, and molecular biological techniques demonstrating multiple receptor subtypes with new properties and functions (Martin, et al., 1994; Wright, et al., 1993). At least 6 .alpha. subunits (.alpha.2-.alpha.7, .alpha.9 in mammals; .alpha.8 in chicks), 3 .beta. subunits (.beta.2-.beta.4), but no .gamma. or .delta. subunits have been cloned in brain. The .alpha.7 subunit, which forms apparent functional homooligomeric receptors (Koike, et al., 1989), is the predominant nicotinic receptor subtype in brain based on quantitative binding studies (couturier, et al, 1990). Its density in hippocampus and neocortex along with the memory-enhancing actions of selective .alpha.7 nicotinic agonists such as 3-(2,4-dimethoxy-benzylidene) anabaseine (DMXB) (Pugh, et al., 1994), indicate a significant role for .alpha.7 receptors in learning and memory. In addition, these receptors are highly permeable to Ca.sup.2+ and rapidly desensitize after activation (Alkondon, et al., 1994; Koike, et al., 1989). These channel properties suggest a modulatory function with respect to neuronal Ca.sup.2+ homeostasis that may account for their reported involvement in synapse formation and neuronal viability (Martin, et al., 1994; Shimohama, et al., in press). Selective .alpha.7 activation has been found to protect neurons against NGF-deprivation in vitro as well as neuronal degeneration following axotomy in vivo. More recently, a mutated .alpha.7 receptor that is incapable of desensitizing has been associated with neurotoxicity in the C. elegans (Treinin and Chalfie, 1995).
1.2.4 Age Related Learning and Memory Loss
The loss of cholinergic neurons in Alzheimer's disease and other neuropathological disorders (e.g., pugilistic dementia; alcohol-induced dementia) is believed to underlie at least some of the memory-deficits observed in these diseases. The loss of these cholinergic neurons in animal models can be prevented using neurotrophic factors, particularly nerve growth factor ("NGF"). NGF has accordingly been developed as a potential therapy for Alzheimer's disease. However, NGF does not cross the blood brain barrier, limiting its usefulness for treating brain-disorders.